Paramyxoviruses include a variety of human pathogens, such as human parainfluenza viruses that cause serious respiratory infections among young children. This group also includes animal pathogens which are similar to the corresponding human virus in structure and sequences, but have distinct host ranges. Little is known about the factors that define the host range of closely related viruses. Our goal is to identify the mechanism(s) that restrict the host range of paramyxovirus using human parainfluenza virus type 1 (hPIV1) and murine parainfluenza virus type 1 (Sendai virus). The hPIV1 and Sendai virus are highly homologous in structure and amino acid sequences but have distinct host species, human vs. mouse. [unreadable] [unreadable] Our preliminary results suggest that hPIV1 requires unidentified host cell factor(s) of human origin for transcription of viral genome. Transcription of viral genome was inefficient in murine cells, suggesting that requirement of a species-specific host cell factor plays a key role in host range restriction of hPIV1. We also found that anti-IFN response of these viruses is species specific, hPIV1 counteracts IFN activity in human cells but not in murine cells, while Sendai virus antagonizes murine IFN activity but not in human cells. These results led us to hypothesize that species specificity of viral anti-IFN activity restrict the host range of type 1parainfluenza viruses. [unreadable] [unreadable] In this project, we will identify the host cell factor(s) required for transcription and evaluate its role in host specificity of hPIV1 in aim 1. Furthermore, we will analyze the molecular mechanism of hPIV1 to antagonize IFN response in aim 2. The species specificity of viral anti-IFN activity and mechanisms of IFN-induced antiviral activities will be characterized in aim 3. We believe that understanding the molecular mechanisms that make virus infectious and pathogenic to humans will significantly contribute to the public health improvement. Our research will also give us clues to develop antiviral reagents that block specific virus-host interactions essential for viral growth in humans. [unreadable] [unreadable] [unreadable] [unreadable]